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Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling
TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depend...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824466/ https://www.ncbi.nlm.nih.gov/pubmed/31582430 http://dx.doi.org/10.1101/gad.330837.119 |
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author | Aragón, Eric Wang, Qiong Zou, Yilong Morgani, Sophie M. Ruiz, Lidia Kaczmarska, Zuzanna Su, Jie Torner, Carles Tian, Lin Hu, Jing Shu, Weiping Agrawal, Saloni Gomes, Tiago Márquez, José A. Hadjantonakis, Anna-Katerina Macias, Maria J. Massagué, Joan |
author_facet | Aragón, Eric Wang, Qiong Zou, Yilong Morgani, Sophie M. Ruiz, Lidia Kaczmarska, Zuzanna Su, Jie Torner, Carles Tian, Lin Hu, Jing Shu, Weiping Agrawal, Saloni Gomes, Tiago Márquez, José A. Hadjantonakis, Anna-Katerina Macias, Maria J. Massagué, Joan |
author_sort | Aragón, Eric |
collection | PubMed |
description | TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-β signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-β signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription. |
format | Online Article Text |
id | pubmed-6824466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-68244662019-11-15 Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling Aragón, Eric Wang, Qiong Zou, Yilong Morgani, Sophie M. Ruiz, Lidia Kaczmarska, Zuzanna Su, Jie Torner, Carles Tian, Lin Hu, Jing Shu, Weiping Agrawal, Saloni Gomes, Tiago Márquez, José A. Hadjantonakis, Anna-Katerina Macias, Maria J. Massagué, Joan Genes Dev Research Paper TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-β signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-β signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription. Cold Spring Harbor Laboratory Press 2019-11-01 /pmc/articles/PMC6824466/ /pubmed/31582430 http://dx.doi.org/10.1101/gad.330837.119 Text en © 2019 Aragón et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Paper Aragón, Eric Wang, Qiong Zou, Yilong Morgani, Sophie M. Ruiz, Lidia Kaczmarska, Zuzanna Su, Jie Torner, Carles Tian, Lin Hu, Jing Shu, Weiping Agrawal, Saloni Gomes, Tiago Márquez, José A. Hadjantonakis, Anna-Katerina Macias, Maria J. Massagué, Joan Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title_full | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title_fullStr | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title_full_unstemmed | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title_short | Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling |
title_sort | structural basis for distinct roles of smad2 and smad3 in foxh1 pioneer-directed tgf-β signaling |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824466/ https://www.ncbi.nlm.nih.gov/pubmed/31582430 http://dx.doi.org/10.1101/gad.330837.119 |
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